Photodynamic therapy (“PDT”) generally involves a local or systemic application of a light-absorbing photosensitive agent, or photosensitizer, which may accumulate selectively in certain target tissues. Upon irradiation with electromagnetic radiation, such as visible light of an appropriate wavelength, reactive oxygen species (e.g., singlet oxygen and/or free radicals) may be produced in cells or other tissue containing the photosensitizer, which promotes cell damage or death. The oxidative damage from these reactive intermediates is generally localized to the cells or structures at which the photosensitizer is present. PDT treatments therefore may be capable of ‘targeting’ specific cells and lesions, for example, if the photosensitizer is present in significant quantity only at desired target sites and/or light activation is performed only at such target sites.
A precursor photosensitizer, such as aminolevulinic acid (“ALA”) or a derivative of ALA such as an ALA-ester, which converts into a photosensitizer (e.g., a porphyrin) when it metabolizes, can also be used in PDT treatments. ALA is an FDA-approved topical PDT agent. ALA is generally the first committed precursor of heme synthesis, and occurs naturally in mammalian cells. When supplied in excess, ALA can overdrive the heme synthesis pathway until intracellular iron stores are depleted, after which photosensitizing porphyrins (e.g., protoporphyrin IX) may accumulate in tissues as originally described, e.g., in Kennedy et al., “Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience,” J Photochem Photobiol B (1990), 6:143-148; Kennedy et al., “Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy,” J Photochem Photobiol B: Biol (1992), 14:275-92; and Kennedy et al., “Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): mechanisms and clinical results,” J Clin Laser Med Surg (1996), 14:289-304.
PDT has been used to treat various medical conditions, including infectious diseases, malignant diseases (such as skin cancers, lymphomas, etc), premalignant conditions (as actinic keratosis), viral warts, hair removal, etc. in many different medical fields, including dermatology, opthalmology, oncology, and others.
For example, ALA-PDT is a potent, long-lasting treatment for severe and scarring acne vulgaris, a common skin disease caused by abnormalities of sebaceous follicles in skin that can lead to permanent scars and disfigurement. PDT is observed to have about the same potency as oral isotretinoin (Accutane®), a very effective treatment. However, isotretinoin, which suppresses sebaceous (oil) gland function in the skin, is dangerous because it may cause birth defects if a woman becomes pregnant during or after taking the drug. PDT treatment can pose a far lower risk than application of oral isotretinoin, is less expensive and has fewer side effects, does not require blood tests, can be used in women of childbearing potential, and can efficiently control severe acne. A course of 1-4 PDT treatments given over 3 months typically inhibits acne for a period varying between several months to permanently. Retreatment can be performed as needed. However, PDT treatment of acne vulgaris using ALA and/or methyl-ALA can have undesirable side effects such as epidermal photosensitization, which causes pain during light exposure, sunburn-like reactions, and/or post-treatment pigmentation as described, e.g., in Hongcharu et al, “Topical ALA-photodynamic therapy for the treatment of acne vulgaris,” J Invest Dermatol, 115, 183-192 (2000).
Although PDT techniques using a photosensitizer or precursor photosensitizer can be effective for certain applications, it is often difficult to control application to the treatment area. For example, the photosensitizer or precursor photosensitizer can be absorbed and/or accumulate in healthy tissues as well as the target tissue. In hair removal, for example, a photosensitizer or precursor photosensitizer that is applied to the skin topically may be absorbed by both the epidermal and dermal layers of the skin. As a result, application of light can cause phototoxicity to the epidermis, which can lead to long-lasting hyperpigmentation or epidermal necrosis. In general, PDT treatments of subepithelial tissue using topically-applied photosensitizers often leads to unwanted damage to the epithelial tissue.
Thermal or chemical inhibition of photosensitizer formation in epithelial tissue from precursors can be used to reduce unwanted damage to such tissue. However, it may be difficult to accurately control the formation and accumulation of photosensitizers in particular tissues and/or tissue layers using thermal or chemical techniques. Also, such techniques can further interfere with the PDT process when using photosensitizers such as ALA.
Accordingly, there is a need for an improved method and apparatus for photodynamic therapy that can reduce or eliminate damage to epithelial tissue in a controllable manner while allowing treatment of underlying targeted tissue.